Post Traumatic Seizure Disorder

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10. Post-Traumatic Seizure Disorder

Robert Teasell MD FRCPC, Nestor Bayona MSc, Corbin Lippert RN-BScN, Shawn Marshall MSc MD FRCPC, Nora Cullen MSc MDFRCPC

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Table of Contents

10.1 Classification of Post-Traumatic Seizures and Epilepsy...... 5

10.2 Incidence of Post-Traumatic Seizures.................................... 6

10.3 Risk Factors for Post-Traumatic Seizures ............................. 6

10.3.1 Identification of the High-Risk Patient ...........................................7

10.4 Natural History of Post-Traumatic Seizures .......................... 8

10.4.1 Onset ....................................................................................................8

10.4.2 Recurrence...........................................................................................8

10.4.3 Summary of Natural History ...............................................................9

10.5 Clinical Picture of Post-Traumatic Seizures .......................... 9

10.6 Complications of Post-Traumatic Seizures ......................... 10

10.6.1 Cognitive and Behavioral Function..................................................10

10.6.2 Influence on Neurologic Recovery...................................................10

10.6.3 Functional Status...............................................................................10

10.6.4 Status Epilepticus..............................................................................11

10.6.5 Mortality..............................................................................................11

10.7 Treatment of Post-Traumatic Seizures................................. 11

10.7.1 Seizure Prevention or Prophylaxis...................................................12

10.7.1.1 Post-Traumatic Seizure Prophylaxis in Children............................21

10.7.2 Surgical Treatment of Post-Traumatic Seizures.............................23

10.8 Summary ................................................................................. 25

Reference List................................................................................. 27

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Table Directory

Table 10.1 Definitions of Post-Traumatic Seizures

Table 10.2 Studies of Risk Factors for Late Post-traumatic Seizures

Table 10.3 Studies of Post-Traumatic Seizure Recurrence

Table 10.4 Summary of Onset and Recurrence of PTS

Table 10.5 Seizure Prevention or Prophylaxis

Table 10.6 Summary of RCT Studies of Seizure Prevention or Prophylaxis

Table 10.7 Summary of non-RCT Studies of Seizure Prevention or Prophylaxis

Table 10.8 Pharmacological Seizure Prevention or Prophylaxis in Childrenfollowing ABI

Table 10.9 Surgical Treatment of Post-Traumatic Seizures

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4

Key Points

Increasing age, alcohol abuse, family history, increasing injury severity,and the occurrence of early seizures immediately after the injury all

increase the risk of developing late post-traumatic seizure disorder.

Later onset seizures have a higher chance of recurrence.

Levetiracetam is as effective as phenytoin in treating and preventingseizures in individuals in the intensive care unit post ABI.

Anticonvulsants provided immediately post-ABI reduce the occurrence ofseizures only within the first week.

Anticonvulsants provided shortly post-ABI do not reduce long-term

mortality, morbidity, or late seizures.

Anticonvulsants have negative consequences on motor tasks.

Early glucocorticoid exposure may increase seizures.

Methylphenidate may not increase the risk of seizures.

Intramuscular midazolam may be effective for acute seizure cessation.

Phenytoin does not reduce early or late seizures in children post-ABI.

Surgical excision can reduce seizures if the focus of the seizures can belocalized.


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10. Post-Traumatic Seizure Disorder

The Brain Injury Special Interest Group of the American Academy of Physical

Medicine and Rehabilitation (1998) have noted that there are approximately422,000 cases of inpatient traumatic brain injuries (TBI) in the United Statesevery year (Kalsbeek et al., 1980). Of all TBI patients who are hospitalized, it isestimated that 5% to 7% will experience post-traumatic seizures (PTS). Thenumber rises to 11% for patients with severe non-penetrating TBI, and up to 35%to 50% for patients with penetrating TBI (Yablon, 1993).

The same group noted that the occurrence of seizures may be associated withaccidental injuries, psychological effects, loss of driving privileges and reducedemployability (Brain Injury SIG 1998). Moreover, there is some theoretical basisto believe that prevention of recurrent early seizures prevents the development of

chronic epilepsy (Yablon 1993) which in turn has prompted the widespread useof prophylactic anticonvulsant treatment in those patients regarded at higher riskof developing PTS even though such treatment may have a negative impact interms of cognitive side effects.

10.1 Classification of Post-Traumatic Seizures and Epilepsy

Post-traumatic seizure disorders have been defined in the Practice Parameter onthe Antiepileptic Drug Treatment of Post-traumatic Seizures by the Brain InjurySpecial Interest Group of the American Academy of Physical Medicine andRehabilitation (see Table below).

Table 10.1 Definitions of Post-Traumatic Seizures (1998)

SeizureDiscrete clinical events that reflect a temporary physiologic dysfunction of the brain characterizedby excessive and hypersynchronous discharge of cortical neurons.

Post-Traumatic SeizureAn initial or recurrent seizure episode not attributable to another obvious cause after penetratingor nonpenetrating TBI. The term post-traumatic seizureis preferred overpost-traumatic epilepsybecause the former encompasses both single and recurrent events.

Immediate Post-Traumatic Seizure

A seizure due to TBI occurring within the first 24 hours of injury

Early Post-Traumatic SeizureA seizure due to TBI occurring within the first week of injury.

Late Post-Traumatic SeizureA seizure due to TBI occurring after the first week of injury.

Post-Traumatic EpilepsyA disorder characterized by recurrent late seizure episodes not attributable to another obvious

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cause in patients following TBI. Although the term post-traumatic epilepsycommonly hasdesignated single or multiple seizures including early seizures, the term should be reserved forrecurrent, late PTS.

Nonepileptic SeizuresEpisodic behavioral events that superficially resemble epileptic attacks but are not associated

with paroxysmal activity within the brain.

Antiepileptic Drug ProphylaxisIn the context of PTS, AED treatment administered to prevent seizures in patients who have notmanifested seizures.

EpilepsyEpilepsy is a condition characterized by recurrent unprovoked seizures.

Practice ParametersResults, in the form of one or more specific recommendations, from a scientifically based analysisof a specific clinical problem.

10.2 Incidence of Post-Traumatic SeizuresTraumatic brain injuries account for 20% of symptomatic epilepsy in the generalpopulation and 5% of all epileptic cases (Yablon & Dostrow, 2001; Hauser et al.,1991). In young adults TBI is the leading cause of epilepsy (Annegers, 1996).

Yablon and Dostrow (2001) have also noted that the overall incidence of lateseizures following non-penetrating TBI among hospitalized patients is 4-7%(Annegers et al., 1980; Jennett, 1975). However, the incidence of PTS is muchhigher on rehabilitation units (as high as 17%) which is felt to reflect theincreased severity of the injury and a higher number of risk factors in this

population (Bontke et al., 1993; Armstrong et al., 1990; Cohen & Groswasser,1991; Kalisky et al., 1985; Ng et al., 2004; Sazbon & Groswasser, 1990) Childrenwith nonpenetrating TBI are less likely to suffer a late post-traumatic seizure(Annegers et al., 1980; Hahn et al., 1988; Kollevol, 1979; Asikainen et al.,1999).In contrast, patients with penetrating TBI experience much higher incidence rates(as high as 35-50%) of post-traumatic seizures (Ascroft, 1941; Caveness & LISS,1961; Caveness et al., 1979; Salazar et al., 1985; Yablon & Dostrow, 2001).

10.3 Risk Factors for Post-Traumatic Seizures

The Brain Injury Special Interest Group of the American Academy of Physical

Medicine and Rehabilitation (1998) has noted that the risk of epilepsy is highestwithin the first two years following brain trauma(Yablon, 1993; Dikmen et al.,1991). There are several patient and injury characteristics that increase thelikelihood of developing PTS.These include a Glasgow Coma Scale score of


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It has been noted that 20% of adults have spontaneous seizures within two yearsof TBI with penetrating injury of the brain, intracranial hematoma, corticalcontusion, depressed skull fracture or a seizure immediately following the onsetof TBI (Temkin et al., 2001). To put this is perspective, Temkin (2001) notes that

this is over 200 times the rate seen in someone who has not suffered a braininjury. Although the risk of developing post-traumatic seizures is highest withinmonths after the injury (Temkin 2001), the risk remains high for individuals withmoderate-severe injuries for as long as 5 years while military personnel sufferingsevere penetrating missile brain injuries show elevated risks for more than 15years after the injury (Weiss et al., 1983; Feeney & Walker, 1979; Annegers etal., 1998; Salazar et al., 1985; Caveness, 1963; Caveness et al., 1979).

10.3.1 Identification of the High-Risk PatientIt is important to identify patients who are at high-risk of developing post-traumatic seizures (PTS) since these patients would benefit greatly from its

prevention or from the impediment of its possible reoccurrence. Yablon andDostrow (2001) have proposed that methods that assess the clinicalcharacteristics of the patient, the injury, and information obtained fromneuroimaging and electrophysiologic assessment techniques can be used toidentify such high-risk patients. Moreover, Yablon and Dostrow (2001) haveidentified some key risk factors which can aid in the identification of thesepatients (Table 10.2).

Table 10.2 Studies of Risk Factors for Late Post-traumatic Seizures (Yablon and Dostrow2001)Risk Factor ReferencePatient Characteristics

Age (Annegers et al., 1980; Asikainen et al., 1999; Hahn et al.,1988; Kollevold, 1979)

Alcohol use (Evans, 1962; Heikkinen et al., 1990; Kollevold, 1978)

Family history (Caveness, 1963; Evans, 1962; Heikkinen et al., 1990;Hendrick & Harris, 1968)

Injury CharacteristicsBone/metal fragments (Ascroft, 1941; Salazar et al., 1985; Walker & Yablon, 1959)

Depresed skull fracture (Jennett, 1975; Hahn et al., 1988; Phillips, 1954; Wiederholt etal., 1989)

Focal contusions/injury (da Silva et al., 1992; De Santis et al., 1992; Eide & Tysnes,1992; Glotzner et al., 1983; Heikkinen et al., 1990)

Focal neurologic deficits (da Silva et al., 1992; Jennett, 1975; Salazar et al., 1985)

Lesion location (da Silva et al., 1992; Evans, 1962; Grafman et al., 1992)

Dural penetration (Caveness & LISS, 1961; Evans, 1962; Salazar et al., 1985)Intracranial hemorrhage (Hahn et al., 1988; Glotzner et al., 1983)

Injury severity (Evans, 1962; Jennett, 1975; Salazar et al., 1985; Walker &Yablon, 1961)

OtherEarly post-traumatic seizures (Heikkinen et al., 1990; Jennett, 1975; Salazar et al., 1985)

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Conclusions:

There are several patient and injury characteristics that increase thelikelihood for the development of late PTS. Some important patientcharacteristics include: increasing age, premorbid alcohol abuse, and

family history. In terms of injury characteristics, markers of increasinginjury severity such as penetrating injuries and depressed skull fractureincrease the risks of late PTS. A seizure occurring immediately after theinjury substantially increases the risk of late PTS. As the severity of thebrain injury increases, the period of time for which a survivor is at risk ofdeveloping PTS also increases.

Increasing age, alcohol abuse, family history, increasing injury severity,and the occurrence of early seizures immediately after the injury allincrease the risk of developing late post-traumatic seizure disorder.

10.4 Natural History of Post-Traumatic Seizures10.4.1 OnsetYablon and Dostrow (2001) have noted that one-half to two-thirds of patients whosuffer PTS will experience seizure onset within the first 12 months, and 75-80%will have seizures by the end of the second year following the injury (Caveness etal., 1979; da Silva et al., 1992; da Silva et al., 1990; Pohlmann-Eden &Bruckmeir, 1997; Salazar et al., 1985; Walker & Yablon, 1959; Walker & Yablon,1961). After 5 years, adults with mild TBI no longer have a significantly increasedrisk relative to the general population (Annegers et al., 1998), whereas patients

with moderate or severe TBI or penetrating TBI remain at increased risk for morethan 5 years post-injury (Annegers et al., 1998; da Silva et al., 1992; Pagni,1990; Salazar et al., 1985).

10.4.2 RecurrenceSeizure recurrence is an important factor in the determination of disability,employment likelihood, quality of life, and increased health care costs (Baker,Nashef, & van Hout, 1997; van Hout et al., 1997; Yablon & Dostrow, 2001).Some studies have reported that following early seizures post-TBI, only one-halfof the patients experienced a recurrence (De Santis et al.,1979; Kollevold, 1979)while another quarter experienced a total of only 2-3 seizures (Kollevold, 1979).

Table 10.3 Studies of Post-Traumatic Seizure RecurrenceAuthors Recurrence IncidenceHaltiner et al.,(1997)

63 adults with moderate or severe TBI and later PTS cumulative incidence ofrecurrent late seizures 86% over 2 yrs; 52% > 4 late seizures, 37% > 9 lateseizures.

Pohlmann-Edenand Bruckmeir(1997)

57 post-traumatic epilepsy patients compared to 50 age and sex-matchedsevere TBI controls Of PTE patients 35% became seizure-free over 3 years;21% had > 1 seizure per week; risk factors poor seizure frequency, missile

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injuries, combined seizure patterns, med noncompliance and alcohol abuse.

10.4.3 Summary of Natural History

The following table provides a summary of the natural history for the onset andrecurrence of post-traumatic seizures as noted by Yablon and Dostrow (2001).

Table 10.4 Summary of Onset and Recurrence of PTSFeature Reference20 30 % of cases of patients with early PTSexperience a late seizure.

(Yablon & Dostrow, 2001)

Seizure onset after the first week shows amuch higher likelihood of seizure recurrence.

(Walker & Yablon, 1961; Haltiner et al., 1997)

Seizure frequency within the first year post-injury may predict future recurrence.

(Salazar et al., 1985)

Persistent PTS may be more common in

partial seizures and less common ingeneralized seizures.

(Salazar et al., 1985)

Immediate PTS is believed to carry noincreased risk of recurrence.

(Jennett, 1975; McCrory et al., 1997)

A small number of patients experiencefrequent seizure recurrences, apparentlyrefractory to conventional anti-seizuretherapy.

(Haltiner et al., 1997; Ng et al., 2004;Pohlmann-Eden & Bruckmeir, 1997)

Some patients may benefit from surgicalintervention.

(Marks et al., 1995; Diaz-Arrastia et al., 2000)

Conclusions

Seizures which occur after the first week of the injury have an increasedchance of seizure recurrence.

Later onset seizures have a higher chance of recurrence.

10.5 Clinical Picture of Post-Traumatic SeizuresWiedemayer et al. (2002) retrospectively analyzed a consecutive series of 1868adult patients with head injury. Brain injury severity was mild in 568 patients

(30.4%), moderate in 681 patients (36.5%), and severe in 619 patients (33.1%).In 109 patients (5.8%), an epileptic seizure occurred in the early post-traumaticperiod; 39 of the 109 patients who experienced an early post-traumatic seizure,suffered from severe head injury, 58 from a moderate head injury, and 12 from amild head injury. Sixty-six early seizures (60.5%) occurred within the first dayfollowing trauma, with a steep decline over the ensuing days. The first epilepticseizure was generalized in 69 patients (63.3%) and focal in 40 patients (36.7%).

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58 patients (53.2%) experienced a second early seizure during the follow-upperiod.

10.6 Complications of Post-Traumatic SeizuresSeizures following TBI may themselves be a source of significant complications

and morbidity and it has been noted that the recurrence of seizures is animportant cause of nonelective hospitalization in patients with severe TBI (Cifu etal., 1999). Potential complications include deterioration in cognitive andbehavioral functioning and overall functional status, influence on neurologicalrecovery, status epilepticus and death.

10.6.1 Cognitive and Behavioral FunctionPost-traumatic seizure disorders may lead to cognitive and behavioural disorders(Yablon & Dostrow, 2001). Cognitive problems may arise during the interictalstate in the absence of active seizures (Aarts et al., 1984; Aldenkamp, 1997;Binnie & Marston, 1992). Patients with PTS experience persistent behavioral

abnormalities and a higher incidence of psychiatric-related hospitalizations evencompared with patients with penetrating TBI who do not experience PTS(Swanson et al.,1995).

10.6.2 Influence on Neurologic RecoveryPost-traumatic seizures can influence neurological recovery (Hernandez &Naritoku, 1997; Yablon & Dostrow, 2001). Yablon and Dostrow (2001) havenoted that in rodent models, brief and infrequent PTS occurring early after braindamage do not appear to impact functional recovery. However, more severe andwidespread seizures occurring within the first 6 days post brain injury result inpermanent impairments of functional recovery; while the same seizures occurring

after the 6 day mark result in no change in somatosensory recovery (Hernandezand Naritoku 1997).

10.6.3 Functional StatusRecurrent PTS may exert a negative impact on functional status following TBI, anadverse effect independent of the severity of the injury (Barlow et al., 2000;Schwab et al., 1993). In the case of penetrating traumatic brain injuries, post-traumatic seizures have been reported to be an important and independent factorwhich affects both employment status and cognitive performance (Schwab et al.1993). However, in the case of nonpenetrating TBI, the impact of PTS onfunctional prognosis and cognition is less clear (Armstrong et al., 1990; Asikainen

et al., 1999). Haltiner et al. (1997) found no significant differences at one year asa consequence of later PTS in terms of neuropsychological performance andpsychosocial functioning when adjusting for injury severity. Asikainen et al.(1999) found that patients with PTS did have poorer outcomes on the GlasgowOutcome Scale, although there were no significant differences in employmentoutcome associated with the presence of PTS.

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10.6.4 Status EpilepticusStatus epilepticus can be defined as either more than 30 minutes of continuousseizure activity (Yablon & Dostrow, 2001) or two or more sequential seizureswithout full recovery of consciousness between seizures (Yablon, 1993). Statusepilepticus is regarded as the most serious of the complications of PTS and may

actually lead to additional neurological damage. Fortunately, clinically apparentstatus epilepticus is an infrequent complication of PTS (Kollevold, 1979).

10.6.5 MortalityYablon and Dostrow (2001) have noted that among patients with PTS mortalityremains consistently elevated (Corkin et al., 1984; Walker & Erculei, 1970;Walker & Blumer, 1989). However, the contribution of PTS to increased moralityis unclear and some studies have suggested that deaths among penetrating TBIpatients with PTS are due to complications of the actual injury and are not relatedto seizures (Rish & Caveness, 1973; Rish et al., 1983).

Yablon and Dostrow (2001) have noted that the complications associated withsingle later post-traumatic seizures are no different than those found in anyseizure and are generally associated with minimal risk. However, the risks ofincreased mortality and increased morbidity in the form of worsened cognitiveand functional prognosis are associated with increasing frequency and severity ofthe seizure disorder.

10.7 Treatment of Post-Traumatic SeizuresSchierhout and Roberts (2001) have reported that a seizure which occurs soonafter a head injury may cause secondary brain damage, due to the increasedmetabolic demands of the brain soon after the injury, increased intracranial

pressure, and excessive amounts of neurotransmitter release which may lead toadditional brain injury. For this reason, the primary therapeutic objective in theuse of anticonvulsant drug has been the prevention of early seizures in anattempt to minimize the extent of brain damage following an injury.

Some anticonvulsant drugs have been shown to have neuroprotective propertiesin animal studies. For example, following hypoxia, phenytoin has been linkedwith reduced neuronal damage in neonatal rats (Vartanian et al., 1996) and in rathippocampal cell cultures (Tasker et al., 1992). Experimental evidence suggeststhat the neuroprotective effects of phenytoin are related to a blockage of voltagedependent sodium channels during hypoxia (Tasker et al. 1992; Vartanian et al.

1996) which would be expected to decrease the spread of calcium inducedneurotoxicity following hypoxic brain injury. As noted by Schierhout and Roberts(2001), this suggests that anti-epileptics may have beneficial properties whichmay be independent of their proposed anti-seizure activity.

Conversely, anti-epileptic drugs have shown toxic effects even in stable patients,with impaired mental and motor function being the most common adverseeffects, although serious adverse effects including deaths as a result of

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hematological reactions have been also reported (Reynolds et al., 1998).Schierhout and Roberts (2001) have suggested that the injured brains responseto anticonvulsants may be such that toxic effects could be more pronounced andneurological recovery may be delayed.

10.7.1 Seizure Prevention or ProphylaxisInitially, retrospective and nonrandomized clinical trials in humans showedfavorable results for the efficacy of anti-epileptic drug prophylaxis (Caveness etal., 1979; Heikkinen et al., 1990; Kollevold, 1978; Murri et al., 1992; Murri et al.,1980; Price, 1980; Rish & Caveness, 1973; Servit & Musil, 1981; Wohns &Wyler, 1979; Young et al., 1979). However, prospective investigations of chronicprophylaxis for late PTS have shown less impressive results (Glotzner et al.,1983; Manaka, 1992; McQueen et al., 1983; Pechadre et al., 1991; Temkin et al.,1990; Temkin et al., 1999; Temkin et al., 1991; Young et al., 1983b; Young et al.,1983a; Formisano et al., 2007; Young et al., 1983b).

Individual Studies

Table 10.5 Seizure Prevention or Prophylaxis

Author/Year/Country/Studydesign/Pedro & D&BScore

Methods Outcome

Szaflarski et al.,(2010)USARCT

PEDro=8D&B=25

N=34 Individuals who has sustained amoderate to severe TBI and remainedin hospital >24 hours, were selected forthe following study and randomly

assigned to either the levetiracetam(LEV) or phenytoin (PHT) group.Those in PHT group were 20mg/kg PEIV maximum of 20000 mg given over60 minutes. The maintenance dosewas 5mg/kg/day IV every 12h. Thosein the LEV group were started on20mg/kg/IV rounded to the nearest 250mg over 60 min then started on amaintenance dose (1000 mg IV every12 h over 15 min). Therapeutic dosewas 1500 mg/12h. GCS, GOS, ICP,DRS were monitored and evaluated.

Duration of treatment for the PHTgroup was 3 to 7 days, for the LEVgroup was 7 days. At time ofdischarge and post discharge therewere no differences in the GOS.There were no differences in ICP,stroke, hypotension, arrhythmia,(etc.) between the two groups. Thosein the LEV group experienced aworsening of their neurological statusless often than the PHT group(p=0.024). Those in the PHT groupexperienced anemia less often thanthe LEV group (p=0.076). DRSscores were lower for those in theLEV group at 3 and 6 months postdischarge. Their GOSE were also

higher at 6 months post intervention.

Formisano et al.,(2007)Italy/USAPre/PostD&B=11

N=137 Two groups were studied, oneretrospectively (n=55) and the otherprosepective (n=83). Patients weregiven anti-epileptic medications for thetreatment of seizures either before orafter they began.

In the retrospective study, theincidence of PTE was lower in thenon-treated group, the time intervalfrom TBI to seizure onset varied. Inthe prospective study the occurrenceof late PTE was higher in patientstreated with an anti-epilepticmedication vs those not treated

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Methods Outcome

(p=0.004). Those who were not

treated with an antiepilepticmedication (n=13) did not develop aseizure disorder. Out of those treatedwith medication (n=69) only 30 showepileptic abnormalities on theirEEGs. Evidence was not found tosupport the use of long-term anti-epileptic medications.

Dikmen et al.,(1991)USARCTPEDro = 6D&B = 24

N=244 Patients who fulfilled at leastone of the following requirements:GCS 10 within 24 hours of injury, CTevidence of cortical contusion,depressed skull fracture,subdural/epdidural/intracerebralhemorrhage, penetrating head wound,seizure within the first 24 hours afterinjury were randomly assigned to betreated with phenytoin or placebo for 1year starting within 24 hours of injury.Initial dose was 20 mg/kgintravenously. Serum levels ofphenytoin were maintained at 3 6mol/l. Outcomes were assessed usinga comprehensive battery ofneuropsychological and psychosocialmeasures at 1, 12, and 24 months

post-injury including: Haltead ReotanNeuropsychological Test Battery,Wechsler Memory Scale, Trails A/Band Stroop test part 1 and 2, SymptomChecklist, Katz Adjustment Scale,Sickness Impact Profile.

In the severely injured (GCS 9)phenytoin significantly impairedneuropsychological performance at 1month as evidenced by the overall

rank-sum type test (p < 0.05). Nosignificant differences inneuropsychological performancewere found between groups in eithermoderately injured (GCS 9)patients at 1 month or in eitherseverity group at 1 year. Patientswho stopped receiving phenytoinbetween 1 and 2 years improvedmore than corresponding placebocases on several measures.Changes in neuropsychologicalmeasures from 12 to 24 monthspost-injury showed that phenytoin

had negative widespread cognitiveeffects compared with placebo onmost measures as evidenced by theoverall rank-sum type test (p < 0.05).

Dikmen et al.,(2000)USARCTPEDro = 8D&B = 25

N=279 Consecutive patients with TBI,admitted within 24 hours post-injury, atrisk of post-traumatic seizures wererandomized to one of three groups: 1)valproic acid (VPA) for 1 monthfollowed by 5 months of placebo 2)Valrproic acid for 6 months or 3)phenytoin (PHT) for 1 week followedby placebo until 6 months post-injury.

Trend towards higher mortality ratein the valproate groups comparedwith phenytoin group (p=0.07).There were no significant differencesat 1, 6 or 12 months on thecomposite measures based on allthe neurospsychological measuresor only on the cognitive measures.

Adjustment for differentialconfounders did not change the lackof significance of the results. Noindividual measure showed asignificant difference among thetreatment groups at 1, 6 or 12months post-injury.

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Methods Outcome

Glotzner et al.,

(1983)GermanyRCTNo Score[German]

N=139 Head injured patients over the

age of 15 were randomized totreatment with carbamazepine on day1 after accident for 1.5 2 years orplacebo. Phenytoin used ifcarbamazepine not tolerated.

Patients on carbamazepine showed

a significant decrease in post-traumatic seizures compared withplacebo (p < 0.05). This differencewas statically significant for earlyseizures (within first week) and forthe follow up time in total, but not forlate seizures.

Manaka (1992)JapanRCTPEDro = 3D&B = 10

N=126 Severe head injury patients (7-88 years of age) who showed either adisturbance of consciousness, bloodycerebrospinal fluid, focal neurologicalsign, depressed fractures or basalfracture, abnormal CT, dural tears,early convulsion, and/or linear fracturewere randomized to receivephenobarbital (10 25 g/ml) or notreatment started 4 weeks after headinjury and continuing for 2 years.Patients were gradually tapered off themedication during the third year.Follow up continued for 5 years.

After a 5-year follow, there were nodifferences in the incidence of lateseizures between severe head injurypatients in the phenobarbital (16%)or the untreated (11%) group.

McQueen et al.,(1983)RCTPEDro = 7

D&B = 20

N=164 Head injured patients (5-65years of age) admitted within < 8 to >30 days post-ABI whose head injurywas complicated by at least one of the

following: dural penetration, intracranialhameatoma, depressed skull fracture,persistent neurological deficit or PTA >24 hours were randomized to receiveeither phenytoin for 1 year or placebo.Patients with early seizures wereexcluded.

No apparent differences betweengroups in the incidence of post-traumatic seizures for up to 24months post-injury; 6 patients in the

phenytoin group and 5 patients in theplacebo group developed post-traumatic epilepsy within one year.

A further 4 patient developedseizures between 1 and 2 years afterinjury.

Pechadre et al.,(1991)RCTPEDro = 3D&B = 14[French]

N=86 head injured patients (3-60 yearsof age) were randomly assigned totreatment with phenytoin (for 3 monthsor one year) or placebo. Phenytointreatment started within the first 24hours following brain injury. Follow-up

continued for 2 years.

After a 2-year follow-up, there was asignificant difference (p< 0.001) inthe incidence of late PTS betweengroups, with the treated patientsshowing an incidence rate of only 6%compared to an incidence rate of

42% in the untreated group.

Smith, Jr. et al.,(1994)RCTPEDro = 6D&B = 22

N=82 ABI patients who had previouslybeen treated with phenytoin (n = 40) orcarbamazepine (n = 42) after theirhead injury and who had beencontinuously maintained on theiranticonvulsant drug for at least 6months prior to this study were

No significant differences were foundbetween patients in the medicationand placebo groups for either drug(phenytoin or carbamazepine) onany of the outcome measures at theend of the placebo phase. Patients inboth drug groups (phenytoin and

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Methods Outcome

randomly assigned to continue their

anticonvulsant therapy or switch to aplacebo for a period of 4 weeks.

A battery of neuropsychological testswas administered during a 4-weekbaseline period (treatment with stabledoses of the patients anticonvulsantcontinued), at the end of a 4 to 5 weekperiod of continued drug treatment orplacebo, and after 4 weeks of notreceiving medication.

carbamazepine) showed significant

improvements (p < 0.01) on severalmeasures of motor and speededperformance following cessation ofanticonvulsant drug treatment.

Temkin et al.,(1990)USARCTPEDro = 6D&B = 24

N=404 Severe ABI patients meeting atleast one of the following criteria:cortical contusion visible on a CT scan,subdural, epidural or intracerebralhematoma, a depressed skull fracture,a penetrating head wound, a seizureswithin 24 hours of injury, or a GCS 10were randomly assigned to treatmentwith phenytoin (n=208) or placebo(n=196) Treatment was started within24 hours of brain injury and continuedfor 1 year with a 2-year follow-up. Initialdose was 20 mg/kg intravenouslywithin 24 hours of injury. Serum levelsof phenytoin were maintained at 36mol/l. The incidence of early (within 1

week) or late (> 8 days after initial drugloading) seizures was comparedbetween groups.

During the first week of treatment,there was a significant reduction in

the number of seizures in thephenytoin group compared with theplacebo group (3.6% vs. 14.2%, p 0.2 for eachcomparison). This lack of late effectcould not be attributed to differentialmortality, low phenytoin levels, ortreatments of some early seizure inpatients assigned go the placebogroup.

Temkin et al.,(1999)USARCTPEDro = 7D&B = 23

N=379 Patients were initially randomlyassigned to one of three groups:phenytoin for 1 week followed byplacebo until 6 months post-injury,Valproate for 1 month followed byplacebo for 5 months, or valproate for6 months. 283 patients were followedup through 2 years. Occurrence of lateseizures (> 7 days after injury) andmortality rates followed up for 2 years.

The rates of early seizures were lowand not significantly different whenusing either valproate or phenytoin(1.5% in the phenytoin group and4.5% in the combined valproategroups, p = 0.14). The rates of lateseizures did not significantly differbetween groups (15% in the 1-weekphenytoin group, 16% in the 1-monthvalproate group, and 24% in the 6-month valproate group, p = 0.19).Mortality rates were not significantlydifferent between groups, but therewas a trend toward higher mortalityrates in the valproate groups (7.2%in the phenytoin groups and 13.4% inthe combined valproate groups, p =0.07).

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Methods Outcome

Young et al.,

(1983a)USARCTPEDro = 6D&B = 23

N=244 Individuals with severe brain

injury patients with either a penetratingmissile wound or a blunt head injurywere randomly assigned to receiveeither Phenytoin or placebo within first24 hours post-injury. The incidence ofearly seizures (within one week ofinjury) between groups was assessed.

There were no significant differences

between groups in the percentage ofearly (within 7 days post-injury)seizures. There was no significantdifference in the interval from injuryto first seizure between the treatedand placebo groups

Young et al.,(1983b)USARCTPEDro = 6D&B = 23

N=179 Same method of randomizationas that employed in Young et al.[1983a]. Initially 214 patients wererandomized, but only 179 patientscompleted the intervention. Theincidence of late seizures betweengroups was compared.

There were no significant differencesbetween groups in the percentage oflate (> 7 days post-injury) seizures.

Servit and Musil(1981)Czechoslovakia

Non-RCTD&B = 8

N=167 Moderate to severe (duration ofloss of conciousness > 1 hour) braininjury patients were divided into twosimilar groups in terms of severity andlocalization of brain injury. The controlgroup (n=24) was treated byconventional methods whereas theother group (n=143) wasprophylactically treated with phenytoin(160-240 mg/day) and phenobarbital(30-50 mg/day) orally for at least 2

years for the prevention of seizures.The incidence of late seizures wascompared between groups.

The incidence of late seizures was25% in the control group (mostoccurring during the first year afterinjury) and 2.1% in theprophylactically treated groupfollowing the discontinuance of drugtherapy (p 24 hours) braininjury patients with documented late

There was no statistically significantdifference in seizure occurrence

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Methods Outcome

USA

Case SeriesD&B = 13

post-traumatic seizures (> 7 days after

injury) who were being treated withmethylphenidate for a variety ofcognitive and behavioral problemsparticipated in this retrospective chartreview. All but 2 of the 30 patientswere receiving concurrentanticonvulsant drug therapy(carbamazepine n = 26, valproic acid n= 2). Any seizure occurrence,anticonvulsant use and other co-medication use was recorded for (1) 3months prior to methylphenidate use(baseline); (2) the duration of

methylphenidate treatment and (3) 3months proceeding methylphenidateuse (follow-up).

while patients were received

methylphenidate compared with theperiod when patients were off thedrug on measures of seizureoccurrence, however there was atrend toward a lesser incidence ofseizures in patients duringmethylphenidate treatment (p =0.063).

Wroblewski &Joseph (1992)USACase StudyNo Score

N=10 Patients who had suffered a TBIresulting from a motor vehicle accident,fall or anoxic encephalopathy receivedintramuscular midazolam after otherbenzodiazepine drugs proved notuseful for acute seizure cessation.Seizure occurrence and behaviouralchanges were assessed.

All patients experienced seizurecessation within minutes ofmidazolam administration. Slight tomoderate sedation were the onlyreported side effects. In thoseindividual treated for behaviouralproblems, midzolan alleviatedagitation and violence with noobvious effects on cognition.

PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002).D&B = Downs and Black (1998) quality assessment scale score

Table 10.6 Summary of RCT Studies of Seizure Prevention or ProphylaxisAuthors/Year Methods ResultsSzaflarski et al.,2010

N = 34 Patients admitted to ICUpost ABI. Phenytoin andlevetiracetam were given to patientswithin 24 hoursof admission

-Levetiracetam was showen to be assafe as phenytoin in reducing seizurespost ABI. Levetiracetam was found tohave fewer side effects and better GOSEoutcomes 3 months post discharge.

Dikmen et al.,(1991)

N = 244 high risk patients.Phenytoin vs. placebo for 1 yearstarting within 24 hours of injury.

- for neuropsychological performance at1-month in severely injured (GCS 9)ND for neuropsychological performancein moderately injured (GCS > 9) at 1-month or either severity group at 1 year.

Dikmen et al.,(2000)

N = 279 of high risk patients.Valproate x 1 mos + placebo x 5mos; valproate x 6 mos; phenytoin x1 wk; + placebo x 6 mos.

Trend towards higher mortality invalproate vs. phenytoin.

Otherwise ND on any measure.

Glotzner et al.,(1983)

N = 139 Carbamazepine at day 1 x1.5-2 years or placebo

+ for early seizuresND for later seizures

Manaka N = 126 Phenobarbital x 2 years vs. ND for late seizures

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(1992) no treatment at all with 5 yearfollow-up.

McQueen et al.,(1983)

N =164 Phenytoin x 1 year.Excluded early seizures.

ND for post-traumatic epilepsy up to 24months post-injury.

Pechadre et al.,(1991)

N = 91 Phenytoin x 3 mos vs. 1year with 2 year follow-up.

+ for late seizures

Smith, Jr. et al.,(1994) N = 82 patients previously treatedwith phenytoin or carbamazepinerandomly assigned to continue onanticonvulsant or switch to placebo

+ for performance on several measuresof motor and speeded performancefollowing cessation of anticonvulsantdrug treatment.

Temkin et al.,(1990)

N = 404 Phenytoin x 1 year vs.placebo with 2 year follow-up.

+ for reduction in seizures in 1st

weekND in seizure occurrence after 1

stweek.

Temkin et al.,(1999)

N = 379 high-risk patients.Phenytoin x 1 week; valrproate x 1mos; valproate x 6 mos. Follow upfor up to 2 years

ND between drugs, both Phenytoin andvalproate + for early seizures.ND between drugs, both negative for lateseizures. Trend toward higher mortality invalproate vs. phenytoin.

Young et al.,(1983a)

N = 244 Severe brain injurypatients. Phenytoin vs. placebowithin 24 hours post-injury.

ND for incidence of early seizures (within7 days post-injury)

Young et al.,(1983b)

N = 214 Phenytoin or placebowithin first 24 hours post-injury.

ND for incidence of late seizures (> 7days post-injury).

ND = No difference between groups; + = Improvement compared with control; - = Impairmentscompared with control

Table 10.7 Summary of non-RCT Studies of Seizure Prevention or ProphylaxisAuthors/Year Methods Results

Formisano et al.,(2007)

N=137 Two groups of patients wereevaluated (one retrospectively andprospectively) after sustaining asevere. Seizure activity wasmonitored in all patients even if ananti-epileptic medication was notprescribed

In both groups PTE was found to belower in the non-treatment group. In theprospective study the occurrence of latePTE was higher in patients treated withan antiepileptic medication than thosenot treated.

Watson et al.,(2004)

N=404 Comparison of TBI patientsexposed or not exposed toglucacorticoids within 1 week ofinjury. Follow up for 2 years.

ND in mortality or late seizures.Early (< 2 days after TBI) exposure toglucocorticoids is associated with higherrisks of seizures.

Wroblewski et al.,(1989)

N=27 Patients with late occurrenceseizures or at high risk for PTS.Taken off phenytoin, phenobarbitalor primidone and treated withcarbamazepine instead.

ND in seizure occurrence between pre-and pos carbamazepine periods.

Wroblewski et al.,(1992)

N=30 ABI patients at risk ofdeveloping seizures who werereceiving anticonvulsant drug

therapy and concurrently receivingmethylphenidate for a variety ofcognitive and behavioural problems.

Trend towards lower frequency ofseizures while on methylphenidate.

Wroblewski andJoseph (1992)

N=10 TBI patients.Treated with intramuscularmidazolan (0.5 20 mg) for acuteseizure cessation.

+ for seizure cessation within minutes ofmidazolan administration

ND = No difference between groups; + = Improvement compared with control

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DiscussionSzaflarski et al. (2010), looked at the effects of levetiracetam (LEV) or phenytoin(PHT) on individuals (n=34) who has sustained a moderate to severe TBI. Allsubjects were randomly assigned to one of two groups the LEV or PHT. Subjectsin the PHT group were administered 20mg/kg PE IV up to a maximum of 20000

mg given over 60 minutes. The PHTs maintenance dose was 5mg/kg/day IVevery 12h and was administered to patients for the next 3-7 days. The LEV groupwas started on 20mg/kg/IV which was rounded to the nearest 250 mg over thefirst 60 minutes. The group was then started on a maintenance dose (1000 mg IVevery 12 h over 15 min) and remained on this for 1-7 days (Szaflarski et al.,2010). The Glasgow Coma Scale (GCS), the Glasgow Outcome Scale (GOS),Intracranial Pressure (ICP) and the Disability Rating Scale were all used toevaluate the groups pre- and post treatment. Results indicate that those on LEVperformed significantly better on the DRS at 3 months (p=0.042) and the GOS at6 months (p=0.039) post intervention compared to the PHT group. There were nodifferences in the number of seizures experienced by study participants

regardless of the group they were assigned to (Szaflarski et al., 2010).

Overall, most published randomized control trials have failed to find anyfavorable evidence for prophylaxis of late PTS (Young et al., 1983a; Glotzner etal., 1983; McQueen et al., 1983; Temkin et al., 1990). In some of these reports,the occurrence of PTS was actually higher in patients treated with anticonvulsantmedications (Young et al.1983b; McQueen et al.1983; Temkin et al.1990;Formisano et al. 2007).

In contrast to late PTS, Yablon and Dostrow (2001) have reported thatanticonvulsant drug prophylaxis consistently reduces the incidence of early PTS(Glotzner et al. 1991; Temkin et al. 1990; Temkin et al. 1999; Younget al.1983a).Similar to most of the studies on late PTS, there is no evidence thatanticonvulsant drug prohylaxis of early seizures reduces the occurrence of latePTS or has any effect on mortality or neurologic disability (Schierhout andRoberts 1998). As mentioned earlier, patients who suffer severe penetratingbrain injuries experience higher risks of PTS. However, due to the small numberof patients with penetrating TBI in most reports, it is not clear if anticonvulsantdrug prophylaxis has any effects, either positive or negative, on the occurrence ofPTS is this subgroup of brain injury patients.

Schierhout and Roberts (2001) conducted a Cochrane review of anti-epilepticdrugs for preventing seizures following acute traumatic brain injury. This reviewof six trials including 1218 randomized patients. The authors noted that all of theincluded trials were restricted to patients considered to be at high risk for PTS.Most of the trials excluded patients who already had one seizure with theintervention started within 24 hours of admission in four trials; the remaining twotrials initiated the intervention between 4 and 8 weeks post head injury. Fourtrials used phenytoin, one trial phenobarbital and one trial carbamazepine. Drugwas provided between 1-2 years in all the trials duration of follow-up was two

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years in most cases. Loss to follow-up ranged from 5-72%. Four trials reportedearly and late seizure; two trials reported late seizures only (Schierhout andRoberts 2001).

The number of patients with early seizures (within the first week after injury) was

available from 4 trials representing 890 randomized subjects. The pooled relativerisk for early seizure prevention was 0.34 (95% CI 0.21, 0.54) with the numberneeded to treat to keep one patient seizure-free in the acute phase was 10.However, there was no evidence that this resulted in a reduction in mortality or areduction in death or persistent vegetative state. The occurrence of late seizurewas not reduced by anti-epileptic prophylaxis at any time. There was insufficientdata to examine non-fatal adverse effect, with the exception of a trend towardsan increased risk of skin rashes.

The authors Schierhout and Roberts (2001) note that, There is no evidence thatprophylactic anti-epileptics used at any time after head injury, reduce death and

disability. There is evidence that prophylactic anti-epileptics reduce earlyseizures, but this is not supported by a reduction in late seizures. Insufficientevidence is available to establish the net benefit of treatment at any time afterhead injury.(pg 1)

There appears to be very little research to evaluate the efficacy ofanticonvulsants given to treat seizures after they have occurred. We identifiedonly one such study in this review. Wroblewski and Joseph (1992) reported on acollection of ten case studies of TBI patients treated with intramuscularmidazolam for acute seizure cessation after other benzodiazepine drugs hadfailed. The authors reported that in all patients, seizures ceased within minutes ofmidazolam administration. Midazolam also prevented the onset of prolongedseizures or status epilepticus. Slight to moderate sedation were the only reportedside effects.

Conclusions:

There is Level 1 evidence to suggest levetiracetam is as safe and effectiveas phenytoin in treatment and prevention of seizures in individuals in theintensive care unit post ABI.

Based on meta-analysis and the findings of this review there is Level 1evidence that anticonvulsants given during the first 24 hours post-ABIreduce the occurrence of early seizures (within the first week post-injury).

There is Level 1 evidence that anticonvulsants given shortly after the onsetof injury, do not reduce mortality or persistent vegetative state or theoccurrence of late seizures (> one week post-injury).

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There is Level 1 evidence that seizure prophylactic treatment with eitherphenytoin or valproic acid results in similar incidences of early or lateseizures and similar mortality rates.

There is Level 1 evidence that both phenytoin and carbamazepine have

negative effects on cognitive performance, particularly on tasks with motorand speed components, which theoretically may have a negative impactupon learning during rehabilitation.

There is Level 2 evidence that glucocorticoid exposure after brain injury isnot associated with a decrease in late seizures, and early exposure (< 2days after injury) is associated with increased seizure activity.

There is Level 4 evidence that methylphenidate for the treatment ofcognitive and behavioral problems can be safely used in brain injuredpatients at risk for posttraumatic seizures as it is not associated with an

increase in seizure frequency.

There is Level 5 evidence that acute intramuscular Midazolam can be usedfor acute seizure cessation.

Levetiracetam is as effective as phenytoin in treating and preventingseizures in individuals in the intensive care unit post ABI.

Anticonvulsants provided immediately post-ABI reduce the occurrence ofseizures only within the first week.

Anticonvulsants provided shortly post-ABI do not reduce long-termmortality, morbidity, or late seizures.

Anticonvulsants have negative consequences on motor tasks.

Early glucocorticoid exposure may increase seizures.

Methylphenidate may not increase the risk of seizures.

Intramuscular midazolam may be effective for acute seizure cessation.

10.7.1.1 Post-Traumatic Seizure Prophylaxis in ChildrenHead injury is reported as the one of the leading causes of morbidity andmortality in children (Young et al., 2004; Kraus et al., 1990). PTS contributes tosecondary injury following head injury and has been commonly observed inchildren with moderate to severe brain injury (Annegers et al., 1980). Childrenare different from adults in terms of mechanism of injury and likely thepathophysiology leading to the development of PTS. Children have been

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reported to react differently to a brain injury than adults, particularly with anincreased amount of significant edema (Aldrich et al., 1992). This may affect thedevelopment of PTS as intracerebral heme deposition has been postulated to bean important mediator in the pathogenesis of both early and late PTS (Willmore,1990). As mentioned earlier, prophylactic anticonvulsants have proved effective

in reducing early PTS in adults and thus it is important to investigate their efficacyin the pediatric population.

Individual Studies

Table 10.8 Pharmacological Seizure Prevention or Prophylaxis in Children following ABI

Author/Year/Country/

Study design/PEDro andD&B Score

Methods Outcome

Young et al.,

(1983)USARCTPEDro = 6D&B = 23

N=41 Pediatric subjects with either a

penetrating missile wound or a blunt headinjury who were admitted within 24 hoursfollowing a severe head injury participated inthis study. Same method of randomizationas that employed in Young et al. 1983[1983a].

There was no significant

difference between groupsregarding the percentage ofchildren having late seizures (> 7days post-injury).

Young et al.,(2004)RCTUSAPEDro= 6D&B = 19

N=102 Children under the age of 16 whoexperienced an acute blunt head injury with amarked alterations in consciousness definedas GCS score 10 for patients 4 yrs of ageor Childrens Coma Scale (CCS) score 9for patients younger than 4 yrs of age, andpulse rate > 60 beats/min were randomized

to phenytoin or placebo within 60 minutes ofpresentation to a pediatric trauma centre.Phenytoin group received initial intravenousloading dose of 18 mg/kg of body weight,infused over 20 minutes. Maintenance dosesof 2 mg/kg of body weight of phenytoin wereadministered every 8 hours for 48 hours for atotal of 5 additional doses. Placebo groupreceived an equivalent volume of the placebosolution.

The occurrence of post-traumaticseizures within 48 hoursbetween groups was compared.No significant differences in theincidence of early post-traumaticseizures within the 48 hoursobservation period between

groups (phenytoin = 7% vs.placebo = 5%).

PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al. 2002).D&B = Downs and Black (1998) quality assessment scale score.

DiscussionWe identified two RCTs investigating the incidence of PTS in pediatric ABIpatients who were prophylactically treated with phenytoin. In the first study,Young et al. (1983c) investigated the incidence of late PTS in 46 children whowere prophylactically treated with phenytoin or placebo within 24 hours of injuryonset. The authors reported that phenytoin was ineffective in reducing theincidence of late seizures compared with placebo. In the more recent study

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conducted by a different group of investigators, Young and colleagues evaluatedthe efficacy of phenytoin in reducing the incidence of early seizures in 102children (Young et al., 2004). Similar to the findings for late seizures, theseauthors reported that phenytoin did not reduce the rate of early seizures.

Conclusions

There is Level 1 evidence that phenytoin does not reduce the occurrence ofearly seizures in children. Moreover, there is also Level 1 evidence fromanother study that phenytoin is ineffective in reducing late seizures inchildren.

Phenytoin does not reduce early or late seizures in children post-ABI.

10.7.2 Surgical Treatment of Post-Traumatic SeizuresYablon and Dostrow (2001) noted the recent interest in a subgroup of ABIpatients who experience continued PTS despite treatment with multiple anti-epileptic drugs. For this special group of patients, surgical treatment may be aviable option.

Individual Studies

Table 10.9 Surgical Treatment of Post-Traumatic Seizures

Author/Year/Country/

Study design/D&B Score

Methodology Outcome

Marks et al.,(1995)USAD&B = 12Case Series

N=25 (17 males: 8 females) headinjuryed patients (mild to severe injuries)who sustained a head injury thatpreceded the onset of seizures and thatwas of sufficient magnitude to causeeither loss of consciousness or PTA.Patients underwent surgical resectionwhen there was sufficient concordance ofpresurgical data (MRI, ictal andintericatal audiovisual and EEGmonitoring, intracarotid amobarbital and

intracranial EEG monitoring) to identifythe seizure focus.

Seizures were successfully localizedin 9 patients. All nine underwentsurgical excision and were seizurefree 1-year post surgery. Theremaining 16 patients did not have afocal MRI lesion and their seizureswere not adequately localized.In those patients who showed afavorable reduction in seizuresfollowing surgical excision, braininjury lesions were specifically limited

to the hippocampus or neocortex.

D&B = Downs and Black (1998) quality assessment scale score.

Surgical Excision of the Post-Traumatic Seizure FocusSome studies have reported a decrease in seizures following resective surgeryamong a selected group of PTE patients (Diaz-Arrastia et al., 2000; Doyle et al.,1996). The major challenge encountered by this treatment approach is the

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accurate localization of the exact region responsible for the development ofseizures, particularly in patients with severe ABI who frequently show multipleand bilateral sites of brain injury (Diaz-Arrastia et al., 2000). Marks et al. (1995)reported that in a cohort of 25 patients with PTS, surgical excision of thepresumed area responsible for PTS resulted in favorable seizure reduction in

less than half of these patients. In those patients who showed a favorablereduction in seizures following surgical excision, brain injury lesions werespecifically limited to the hippocampus or neocortex (Marks et al., 1995) thus,making the identification and excision more accurate. Thus, surgical excision ofthe post-traumatic seizure focus may only be a viable treatment option for asubgroup of ABI patients in whom the site of the brain injury lesion can beaccurately identified, thus excluding patients suffering severe ABI with multipleand bilateral localization of brain injury.

Conclusions

There is Level 4 evidenced that a subgroup of ABI patients where theseizure focus can be accurately localized would benefit from surgicalexcision.

Surgical excision can reduce seizures if the focus of the seizures can belocalized.

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10.8 Summary

1. There are several patient and injury characteristics that increase thelikelihood for the development of late PTS. Some important patientcharacteristics include: increasing age, premorbid alcohol abuse,

and family history. In terms of injury characteristics, markers ofincreasing injury severity such as penetrating injuries and depressedskull fracture increase the risks of late PTS. A seizure occurringimmediately after the injury substantially increases the risk of latePTS. As the severity of the brain injury increases, the period of timefor which a survivor is at risk of developing PTS also increases.

2. Seizures which occur after the first week of the injury have anincreased chance of seizure recurrence.

3. There is Level 1 evidence to suggest levetiracetam is as safe and

effective as phenytoin in treatment and prevention of seizures in theintensive care unit in individuals post ABI.

4. Based on meta-analysis and the findings of this review there is Level1 evidence that anticonvulsants given during the first 24 hours post-ABI reduce the occurrence of early seizures (within the first weekpost-injury).

5. There is Level 1 evidence that anticonvulsants given shortly after theonset of injury, do not reduce mortality or persistent vegetative stateor the occurrence of late seizures (> one week post-injury).

6. There is Level 1 evidence that seizure prophylactic treatment witheither phenytoin or valproic acid results in similar incidences of earlyor late seizures and similar mortality rates.

7. There is Level 1 evidence that both phenytoin and carbamazepinehave negative effects on cognitive performance, particularly on taskswith motor and speed components, which theoretically may have anegative impact upon learning during rehabilitation.

8. There is Level 2 evidence that glucocorticoid exposure after brain

injury is not associated with a decrease in late seizures, and earlyexposure (< 2 days after injury) is associated with increased seizureactivity.

9. There is Level 4 evidence that methylphenidate for the treatment ofcognitive and behavioral problems can be safely used in braininjured patients at risk for posttraumatic seizures as it is notassociated with an increase in seizure frequency.

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26

10. There is Level 5 evidence that acute intramuscular midazolam can be

for acute seizure cessation.

11. There is Level 1 evidence from one study that phenytoin does not

reduce the occurrence of early seizures in children. Moreover, thereis also Level 1 evidence from another that phenytoin is ineffective inreducing late seizures in children.

12. There is Level 4 evidenced that a subgroup of ABI patients where theseizure focus can be accurately localized would benefit from surgicalexcision.


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